Excision repair cross-complementing 1 expression protects against ischemic injury following middle cerebral artery occlusion in the rat brain

Abstract

To study the effects of excision repair cross-complementing 1 (ERCC1) on the pathophysiological process of brain ischemia, we examined the changes in ERCC1 expression, as well as the functional significance of ERCC1 in the rat brain following middle cerebral artery occlusion (MCAO). The results were as follows: (1) ERCC1 immunopositive cells were widely distributed in various brain regions. ERCC1 expression was localized to the nuclei of neurons and astrocytes. (2) ERCC1 expression, as determined by western blot, increased at 3 days, remaining until 14 days, in the ipsilateral cortex and striatum following MCAO. Immunohistochemical analysis demonstrated that ischemia induced increased ERCC1 expression within the periinfarct core, with increasingly less expression toward the core. (3) Knockdown of ERCC1 expression by intraventricular injection of antisense plasmids increased DNA damage and infarct volume in the ischemic brain. (4) ERCC1 overproduction, by injection of expression plasmids, significantly reduced infarct volume and the accumulation of DNA-damaged neurons. Taken together, these results indicate that both endogenous ERCC1 and exogenous ERCC1 have an important neuroprotective function in the brain. In addition, administration of ERCC1 to the brain could prove to be a successful strategy for neuronal protection against ischemic injury.

Polymorphism in ERCC1 confers susceptibility of coronary artery disease and severity of coronary artery atherosclerosis in a Chinese Han population

“…This result was supported by a recent study that knockdown of ERCC1 expression exhibited an increasing infarct volume in the ischemic rat brain 12 and the report that ERCC1-deficient mice showed increased vascular stiffness and vascular dysfunction 13 . Therefore, combined with the association of SNP rs11615 with ERCC1 expression, we speculated that SNP rs11615 might accelerate the progress of coronary artery atherosclerosis.…”

“…ERCC1 is mainly responsible for making incision at the 5′ terminus of DNA lesions by forming a structure-specific endonuclease complex with xeroderma pigmentosum complementation group F (XPF) and may contribute to positioning the nuclease complex at the lesion site by interacting with Xeroderma pigmentosum complementation group A (XPA) 9 . Besides evidence of molecular studies, in animal model studies, the knockdown and overexpression of ERCC1 was related highly to the increase and decrease of infarct volume in the ischemic brain respectively 12 . Mice with ERCC1 deficiency showed vascular dysfunctions, including elevated blood pressure and increased vascular stiffness 13 and also led to elevated serum cholesterol level and the expression change of genes involved in metabolism of cholesterol, which have been considered as traditional risk factors for CAD 14, 15 .…”

Oxidative stress and DNA damage after cerebral ischemia: Potential therapeutic targets to repair the genome and improve stroke recovery

“…The expression of ERCC1, the rate-limiting component of NER, increases in the ipsilateral cortex and striatum 3–14 days after middle cerebral artery occlusion. Knocking out ERCC1 expression by injecting antisense plasmids increases DNA damage in neurons and promotes infarct sizes after stroke (He et al, 2009). These findings support the view that coordinated DNA repair is essential to complete ischemic recovery.…”

Mechanistic Insight into DNA Damage and Repair in Ischemic Stroke: Exploiting the Base Excision Repair Pathway as a Model of Neuroprotection

“…It was then demonstrated that preischemic treatment of adenovirus-APE diminished the nuclear accumulation of AP site lesions and 8-OHdG, and significantly decreased TUNEL-positive cells and infarct volume after ischemia=reperfusion injury (41). Another study showed that ERCC1 overexpression, by injection of the expression plasmids into the rat brain, significantly reduced the accumulation of DNA-damaged neurons and ischemic cell death after MCAO (31). Given the relatively acute nature of cell death after stroke and the small time window of opportunity for stroke treatment, gene delivery, which needs relatively long time to take effect, may not be a legitimate therapeutic strategy for ischemic stroke.…”

“…Overexpression of ERCC1, by injection of expression plasmids, significantly reduced the accumulation of DNA-damaged neurons and ischemic injury. In contrast, reduced endogenous ERCC1 levels, produced by specific antisense, increased DNA damage accumulation and ischemic brain damage following middle cerebral artery occlusion (MCAO), a transient focal cerebral ischemia model (31).…”